Gene expression in the dorsal root ganglion and the cerebrospinal fluid metabolome in polyneuropathy and opioid tolerance in rats

• Published in: IBRO neuroscience reports Vol. 17; pp. 38 - 51
• Main Authors: Ahlström, Fredrik H.G., Viisanen, Hanna, Karhinen, Leena, Velagapudi, Vidya, Blomqvist, Kim J., Lilius, Tuomas O., Rauhala, Pekka V., Kalso, Eija A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.12.2024; Elsevier
• Subjects: cerebrospinal fluid; dorsal root ganglion; Neuropathic pain; opioid tolerance; Research Paper; NP; opioid tolerance; CSF; dorsal root ganglion; cerebrospinal fluid; DRG; STZ; CNS; Neuropathic pain
• ISSN: 2667-2421; 2667-2421
• DOI: 10.1016/j.ibneur.2024.05.006

First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve sufficient analgesia with these drugs. Opioids are considered third-line analgesics in NP due to potential severe and unpredictable adverse effects in long-term use. Also, opioid tolerance and NP may have shared mechanisms, raising further concerns about opioid use in NP. We set out to further elucidate possible shared and separate mechanisms after chronic morphine treatment and oxaliplatin-induced and diabetic polyneuropathies, and to identify potential diagnostic markers and therapeutic targets. We analysed thermal nociceptive behaviour, the transcriptome of dorsal root ganglia (DRG) and the metabolome of cerebrospinal fluid (CSF) in these three conditions, in rats. Several genes were differentially expressed, most following oxaliplatin and least after chronic morphine treatment, compared with saline-treated rats. A few genes were differentially expressed in the DRGs in all three models (e.g. Csf3r and Fkbp5). Some, e.g. Alox15 and Slc12a5, were differentially expressed in both diabetic and oxaliplatin models. Other differentially expressed genes were associated with nociception, inflammation, and glial cells. The CSF metabolome was most significantly affected in the diabetic rats. Interestingly, we saw changes in nicotinamide metabolism, which has been associated with opioid addiction and withdrawal, in the CSF of morphine-tolerant rats. Our results offer new hypotheses for the pathophysiology and treatment of NP and opioid tolerance. In particular, the role of nicotinamide metabolism in opioid addiction deserves further study. •Fkbp5 and Csf3r were differentially expressed in all models.•Many genes related to nociception and inflammation were affected by the treatments.•Our study is the first to characterize the CSF metabolome in these animal models.•Nicotinamide levels in the CSF rose greatly following chronic morphine treatment.•Nicotinamide is thought to be of importance in opioid addiction and withdrawal.